Methamphetamine abuse is a widespread problem for which there is currently no effective pharmacotherapy. This project will test the safety and efficacy of medications that modulate adrenergic function as treatments for methamphetamine dependence. In a coordinated series of inpatient laboratory and outpatient treatment studies, we will perform a systematic investigation of the utility of adrenergic compounds. The specific compounds that we propose examining are the alpha-2 agonist clonidine, the beta-blocker carvedilol, the alpha-l antagonist prazosin, and the norepinephrine reuptake inhibitor atomoxetine. As part of our research, we will develop new assay techniques and utilize population pharmacokinetic/pharmacodynamic modeling to provide a quantitative estimate of the amounts of illicit methamphetamine consumed during our trials. We postulate that quantifying the effects of candidate pharmacotherapies on illicit drug intake will substantially improve our ability to assess the effectiveness of our medications and therapeutic outcomes. Relapse to drug use occurs as a function of complex alterations in mood, craving, stress and withdrawal symptomatology. Surrogate markers can be essential in determining drug response. In our studies we will assess the utility of using the cytokines IL-6, C-reactive protein and tumor necrosis factor-alpha as surrogate makers of stress to predict relapse, measure drug effect, and determine outcome. Specific experiments are coordinated so that results from one experiment informs the design of subsequent, studies. In our laboratory component we will) assess interactions between our candidate drugs and methamphetamine, 2) develop and validate under controlled conditions our method to quantify illicit drug intake, and 3) evaluate methamphetamine-cytokine interactions. Results from these studies are used to advance two of the four adrenergic drugs from the inpatient laboratory to placebo-controlled outpatient treatment trials. In these outpatient trials we will 1) assess the clinical efficacy of these candidate drugs, 2) validate the quantitative methamphetamine ingestion method under real world conditions, and 3) determine the utility of our immune markers to predict relapse. Our focused, mechanistically-based studies present opportunities for methods development and efficacy evaluations that could not be practically achieved without a collaborative center.